Alzheimer's disease (AD) is estimated to afflict more than 20 million people worldwide and is believed to be the most common cause of dementia. As the World population ages, the number of people with Alzheimer's disease (AD), currently approximately 5.4 million in the United States, will continue to rise. Alzheimer's is a neurodegenerative disease associated with progressive dementia and memory loss. Two key characteristics of AD are the accumulation of extracellular deposits containing aggregated Aβ peptide and neuronal synaptic loss in the AD in specific brain regions. Although AD pathogenesis is complex, compelling genetic and biochemical evidence suggest that overproduction of Aβ, or failure to clear this peptide is the earliest event in the amyloid cascade that lead to AD primarily through amyloid deposition, which is presumed to be involved in neurofibrillary tangle formation, neuronal dysfunction and microglia activation, that characterize AD-affected brain tissues.
Neurofibrillary tangles, along with plaques comprised of Aβ peptide, are a pathological hallmark of Alzheimer's Disease (AD). Hyperphosphorylation of the microtubule-stabilizing protein tau leads to tangle formation. In people diagnosed with AD, and in our hands using the J20 mouse model of AD, the level of tau phosphorylation has the closest correlation to cognitive impairment. The reversal of tau pathology alone can improve memory, even in the presence of high Aβ42 in J20 mice (Roberson, et al. (2007) Science, 316(5825): 750-754). Even when Aβ plaque load is similar, reduction in tau expression and therefore tau pathology (tau-) increases performance in the Morris Water Maze. Tau pathology is “downstream” of Aβ formation in that Aβ increases expression of glycogen synthase kinase 3beta (GSK-3β), an enzyme that can increase phosphorylation of tau. The isoform of Aβ, whether soluble, oligomeric, and/or plaque-bound likely affects GSK-3β expression, therefore absolute AB level may not be directly related to p-tau level. Convergent evidence implicates stress in AD neuropathology (Carroll, et al. (2011) J. Neurosci. (40): 14436-14449). Stress exposure can increase Aβ production and induce deficits in hippocampal cell proliferation and contextual memory (Wilson et al. (2003) Neurology, 61: 1479-1485). Moreover, exposure to a variety of physiological stressors can activate tau kinases and induce tau phosphorylation (tau-P) in rodents (Dong et al. (2004) Neurosci., 127: 601-609). The corticotropin releasing factor (CRF) signaling system plays a role in response to stress (Kang et al. (2007) Proc. Natl. Acad. Sci. USA, 104: 10673-10678).